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ARS Home » Pacific West Area » Davis, California » Western Human Nutrition Research Center » Obesity and Metabolism Research » Research » Publications at this Location » Publication #346154
Title: Dose-related liver injury of Geniposide associated with the alteration in bile acid synthesis and transportation

Author
item TIAN, JINGZHUO - Chinese Academy Of Medical Sciences
item ZHU, JINGJING - Chinese Academy Of Medical Sciences
item YI, YAN - Chinese Academy Of Medical Sciences
item LI, CHUNYING - Chinese Academy Of Medical Sciences
item ZHANG, YUSHI - Chinese Academy Of Medical Sciences
item ZHAO, YONG - Chinese Academy Of Medical Sciences
item PAN, CHEN - Chinese Academy Of Medical Sciences
item XIANG, SHIXIE - Chinese Academy Of Medical Sciences
item LI, XIAOLONG - Chinese Academy Of Medical Sciences
item LI, JING - Chinese Academy Of Medical Sciences
item Newman, John
item FENG, XIAOYI - Chinese Academy Of Medical Sciences
item LIU, JING - Chinese Academy Of Medical Sciences
item HAN, JIAYIN - Chinese Academy Of Medical Sciences
item WANG, LIANMEI - Chinese Academy Of Medical Sciences
item LA FRANO, MICHAEL - University Of California, Davis
item LIANG, AIHUA - Chinese Academy Of Medical Sciences

Submitted to: Scientific Reports
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 6/28/2017
Publication Date: 8/21/2017
Citation: Tian, J., Zhu, J., Yi, Y., Li, C., Zhang, Y., Zhao, Y., Pan, C., Xiang, S., Li, X., Li, J., Newman, J.W., Feng, X., Liu, J., Han, J., Wang, L., La Frano, M.R., Liang, A. 2017. Dose-related liver injury of Geniposide associated with the alteration in bile acid synthesis and transportation. Scientific Reports. 7:8938. https://doi.org/10.1038/s41598-017-09131-2.
DOI: https://doi.org/10.1038/s41598-017-09131-2

Interpretive Summary: Geniposide is the major active ingredient in the Chinese medicinal herb Fructus Gardenia (FG) widely used for treating jaundice, diarrhea, and gastroenteritis. While clinical FG toxicity has not been reported, animal studies show that both FG and Geniposide can cause liver toxicity. To identify biomarkers of liver damage associated with Geniposide exposure, we collected blood from male Sprague-Dawley rats after 3-days of intragastric administration of either 100 mg/kg or 300 mg/kg of Geniposide. Changes in liver tissue structure, serum concentrations of liver enzymes, serum and liver bile acid profiles, and hepatic bile acid synthesis and transportation gene expression were measured. The 300 mg/kg Geniposide caused liver injury as indicated by pathological changes in tissue structure, increases in serum liver enzymes, and increases of liver total bile acid concentrations of 75%, with increases dominated by the taurine-conjugated bile acids. The 300 mg/kg Geniposide also down-regulated the expression of proteins important in bile acid signaling and a major bile salt export pump. In conclusion, 300 mg/kg Geniposide can induce liver injury in the rat with associated changes in bile acid regulating genes, leading to an accumulation of taurine conjugates in the rat liver. Serum levels of taurine-conjugated bile acids are potential markers of Geniposide-induced liver damage.

Technical Abstract: Fructus Gardenia (FG), containing the major active constituent Geniposide, is widely used in China for medicinal purposes. Currently, clinical reports of FG toxicity have not been published, however, animal studies have shown FG or Geniposide can cause hepatotoxicity in rats. We investigated Geniposideinduced hepatic injury in male Sprague-Dawley rats after 3-day intragastric administration of 100 mg/kg or 300 mg/kg Geniposide. Changes in hepatic histomorphology, serum liver enzyme, serum and hepatic bile acid profiles, and hepatic bile acid synthesis and transportation gene expression were measured. The 300 mg/kg Geniposide caused liver injury evidenced by pathological changes and increases in serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP) and '-glutamytransferase ('-GT). While liver, but not sera, total bile acids (TBAs) were increased 75% by this dose, dominated by increases in taurine-conjugated bile acids (t-CBAs). The 300 mg/kg Geniposide also down-regulated expression of Farnesoid X receptor (FXR), small heterodimer partner (SHP) and bile salt export pump (BSEP). In conclusion, 300 mg/kg Geniposide can induce liver injury with associated changes in bile acid regulating genes, leading to an accumulation of taurine conjugates in the rat liver. Taurocholic acid (TCA), taurochenodeoxycholic acid (TCDCA) as well as tauro-a-muricholic acid (T-a-MCA) are potential markers for Geniposide-induced hepatic damage.